Prospective studies have shown that smokers whoa re vulnerable to depression are less successful at quitting and have a higher relapse rate than euthymic smokers. Seventy-five percent of smokers with a history of depression develop depression during smoking cessation, even if they are not depressed prior to quitting Nicotine, a principal component of cigarette smoke, has been suggested to have rapid-acting antidepressant effects in non-smokers. These effects of nicotine are mediated through its initial actions on a central nicotinic acetylcholine receptor (nAChR) and the downstream enhancement of serotonin (5-HT) neurotransmission. In addition, a unknown byproduct of tobacco smoke is a potent monoamine oxidase inhibitor which further enhances 5-HT function. Since cigarette smoke has potent effectors on 5-HT, synaptic markers for this transmitter may by differentially regulated in smokers versus non-smokers. Also, the emergence of depression during smoking cessation in vulnerable smokers may be a consequence of adaptive changes in 5-HT markers. In vivo imaging using radiotracers regionally selective for the 5-HT transporter and 5-HT2A receptor have demonstrated reduced numbers of these pre- and post-synaptic 5-HT markers in living depressed patients. We hypothesize that heavy cigarette smoking will induce adaptive changes in 5-HT markers in living depressed patients. We demonstrated reduced numbers of these pre- and postsynaptic 5-HT markers in living depressed patients. We hypothesize that heavy cigarette smoking will induce adaptive changes in 5-HT transporter and 5-HT2A receptor number in smokers, and that these 5-HT markers will down-regulate during smoking cessation in the subset of smokers vulnerable to depression. To test this hypothesis, we propose the following specific aims: 1) to determine the effects of smoking on 5-HT transporters and 5-HT2A receptors in euthymic smokers and non-smokers between genders 2) to determine if 5- HT-transporters and 5-HT2A receptors undergo adaptive changes during smoking cessation in smokers that develop depression; and 3) to develop a radiotracer for in vivo imaging of the nAChR, so that its potential role in nicotine dependence and depression may be studied in living smokers. The results from these studies will determine if there is a difference in pre- and postsynaptic 5-HT in smokers and if adaptations in key 5-HT markers during withdrawal are correlated with the emergence of depressive symptoms in vulnerable smokers. Furthermore, these studies may elucidate a neurochemical marker which will identify a subgroup of smokers who would benefit from antidepressant treatment during smoking cessation.